Hiv replication inhibiting pyrimidines

ABSTRACT

This invention concerns the use of compounds of formula  
                 
 
     the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein -a 1 =-a 2 -a 3 =a 4 - forms a phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl with the attached vinyl group; n is 0 to 4; and where possible 5; R 1  is hydrogen, aryl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxy-carbonyl, substituted C 1-6 alkyl, or substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; each R 2  independently is hydroxy, halo, optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalo-methylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or a 5-membered heterocyclic ring; p is 1 or 2; L is optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-7 cycloalkyl; or L is —X—R 3  wherein R 3  is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; X is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or —S(═O) 2 —; Q is hydrogen, C 1-6 alkyl, halo, polyhalo-C 1-6 alkyl or an optionally substituted amino group; Y represents hydroxy, halo, C 3-7 cycloalkyl, optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or aryl; aryl is optionally substituted phenyl; Het is an optionally substituted heterocyclic radical; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.

[0001] The present invention concerns the use of pyrimidine derivativeshaving Human Immunodeficiency Virus (HIV) replication inhibitingproperties. It also relates to a novel group of pyrimidine derivatives,their use as a medicine, their processes for preparation andpharmaceutical compositions comprising them.

[0002] EP-0,834,507 discloses substituted diamino 1,3,5-triazinederivatives having HIV replication inhibiting properties. The presentcompounds differ from the known 1,3,5-triazines by structure and bytheir improved HIV replication inhibiting properties.

[0003] The present invention is concerned with the use of compounds offormula (I)

[0004] the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines and the stereochemically isomeric forms thereof,wherein

[0005] -a¹=a²-a³=a⁴- represents a bivalent radical of formula

—CH═CH—CH═CH—  (a-1);

—N═CH—CH═CH—  (a-2);

—N═CH—N═CH—  (a-3);

—N═CH—CH═N—  (a-4);

—N═N—CH═CH—  (a-5);

[0006] n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then nmay also be 5;

[0007] R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;

[0008] each R² independently is hydroxy, halo, C₁₋₆alkyl optionallysubstituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyloptionally substituted with one or more halogen atoms or cyano,C₂₋₆alkynyl optionally substituted with one or more halogen atoms orcyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

[0009] wherein each A independently is N, CH or CR⁶;

[0010] B is NH, O, S or NR⁶;

[0011] p is 1 or 2; and

[0012] R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

[0013] L is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,whereby each of said aliphatic group may be substituted with one or twosubstituents independently selected from

[0014] C₃₋₇cycloalkyl,

[0015] indolyl or isoindolyl, each optionally substituted with one, two,three or four substituents each independently selected from halo,C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl,

[0016] phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, whereineach of said aromatic rings may optionally be substituted with one, two,three, four or five substituents each independently selected from thesubstituents defined in R²; or

[0017] L is —X—R³ wherein

[0018] R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,wherein each of said aromatic rings may optionally be substituted withone, two, three, four or five substituents each independently selectedfrom the substituents defined in R²; and

[0019] X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or—S(═O)₂—;

[0020] Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or—NR⁴R⁵; and

[0021] R⁴ and R⁵ are each independently selected from hydrogen, hydroxy,C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl,aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono- ordi(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶,—C(═O)R⁶, —NHC(═O)H, —C(═O)NNNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het;or

[0022] R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;

[0023] Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyloptionally substituted with one or more halogen atoms, C₂₋₆alkynyloptionally substituted with one or more halogen atoms, C₁₋₆alkylsubstituted with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,—C(═NH)R⁶or aryl;

[0024] aryl is phenyl or phenyl substituted with one, two, three, fouror five substituents each independently selected from halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl andpolyhaloC₁₋₆alkyloxy;

[0025] Het is an aliphatic or aromatic heterocyclic radical; saidaliphatic heterocyclic radical is selected from pyrrolidinyl,piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphaticheterocyclic radical may optionally be substituted with an oxo group;and said aromatic hetero-cyclic radical is selected from pyrrolyl,furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinylwherein each of said aromatic heterocyclic radical may optionally besubstituted with hydroxy;

[0026] for the manufacture of a medicine for the treatment of subjectssuffering from HIV (Human Immunodeficiency Virus) infection.

[0027] The present invention also relates to a method of treatingwarm-blooded animals suffering from HIV (Human Immunodeficiency Virus)infection. Said method comprises the administration of a therapeuticallyeffective amount of a compound of formula (I) or a N-oxide form, apharmaceutically acceptable addition salt or a stereochemically isomericform thereof in admixture with a pharmaceutical carrier.

[0028] This invention also relates to novel compounds having the formula

[0029] the N-oxides, the addition salts, the quaternary amines and thestereochemically isomeric forms thereof, wherein

[0030] -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula

—CH═CH—C(R^(2a))═CH—CH═  (b-1);

—N═CH—C(R^(2a))═CH—CH═  (b-2);

—CH═N—C(R^(2a))═CH—CH═  (b-3);

—N═CH—C(R^(2a))═N—CH═  (b-4);

—N═CH—C(R^(2a))═CH—N═  (b-5);

—CH═N—C(R^(2a))═N—CH═  (b-6);

—N═N—C(R^(2a))═CH—CH═  (b-7);

[0031] q is 0, 1, 2; or where possible q is 3 or 4;

[0032] R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;

[0033] R^(2a) is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl,C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- ordi(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano, orC₂₋₆alkynyl substituted with cyano;

[0034] each R² independently is hydroxy, halo, C₁₋₆alkyl optionallysubstituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyloptionally substituted with one or more halogen atoms or cyano,C₂₋₆alkynyl optionally substituted with one or more halogen atoms orcyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

[0035] wherein each A independently is N, CH or CR⁶;

[0036] B is NH, O, S or NR⁶;

[0037] p is 1 or 2; and

[0038] R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

[0039] L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,whereby each of said aliphatic group may be substituted with one or twosubstituents independently selected from

[0040] C₃₋₇cycloalkyl,

[0041] indolyl or isoindolyl, each optionally substituted with one, two,three or four substituents each independently selected from halo,C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl,

[0042] phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, whereineach of said aromatic rings may optionally be substituted with one, two,three, four or five substituents each independently selected from thesubstituents defined in R²; or

[0043] L is —X—R³ wherein

[0044] R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,wherein each of said aromatic rings may optionally be substituted withone, two, three, four or five substituents each independently selectedfrom the substituents defined in R²; and

[0045] X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or—S(═O)₂—;

[0046] Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or—NR⁴R⁵; and

[0047] R⁴ and R⁵ are each independently selected from hydrogen, hydroxy,C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl,aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono- ordi(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶,—C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het;or

[0048] R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;

[0049] Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyloptionally substituted with one or more halogen atoms, C₂₋₆alkynyloptionally substituted with one or more halogen atoms, C₁₋₆alkylsubstituted with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶or aryl;

[0050] aryl is phenyl or phenyl substituted with one, two, three, fouror five substituents each independently selected from halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl andpolyhaloC₁₋₆alkyloxy;

[0051] Het is an aliphatic or aromatic heterocyclic radical; saidaliphatic heterocyclic radical is selected from pyrrolidinyl,piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphaticheterocyclic radical may optionally be substituted with an oxo group;and said aromatic heterocyclic radical is selected from pyrrolyl,furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinylwherein each of said aromatic heterocyclic radical may optionally besubstituted with hydroxy.

[0052] As used herein C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl,pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C₁₋₁₀alkyl asa group or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 10 carbon atoms such as the groupsdefined for C₁₋₆alkyl and heptyl, octyl, nonyl, decyl and the like;C₁₋₁₂alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 12 carbon atomssuch as the groups defined for C₁₋₁₀alkyl and undecyl, dodecyl and thelike; C₁₋₄alkylidene defines straight or branched chain saturatedbivalent hydro-carbon radicals having from 1 to 4 carbon atoms such asmethylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or1,3-propylidene, 1,4-butanediyl or 1,4-butylidene and the like;C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms containing adouble bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl andthe like; C₂₋₁₀alkenyl defines straight and branched chain hydrocarbonradicals having from 2 to 10 carbon atoms containing a double bond suchas the groups defined for C₂₋₆alkenyl and heptenyl, octenyl, nonenyl,decenyl and the like; C₂₋₆alkynyl defines straight and branched chainhydrocarbon radicals having from 2 to 6 carbon atoms containing a triplebond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like;C₂₋₁₀alkynyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 10 carbon atoms containing a triple bond such as thegroups defined for C₂₋₆alkynyl and heptynyl, octynyl, nonynyl, decynyland the like.

[0053] As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide group when attached once to asulfur atom, and a sulfonyl group when attached twice to a sulfur atom.

[0054] The term halo is generic to fluoro, chloro, bromo and iodo. Asused in the foregoing and hereinafter, polyhalomethyl as a group or partof a group is defined as mono- or polyhalosubstituted methyl, inparticular methyl with one or more fluoro atoms, for example,difluoromethyl or trifluoromethyl; polyhaloC₁₋₆alkyl as a group or partof a group is defined as mono- or polyhalosubstituted C₁₋₆alkyl, forexample, the groups defined in halomethyl, 1,1-difluoro-ethyl and thelike. In case more than one halogen atoms are attached to an alkyl groupwithin the definition of polyhalomethyl or polyhaloC₁₋₆alkyl, they maybe the same or different.

[0055] Het is meant to include all the possible isomeric forms of theheterocycles mentioned in the definition of Het, for instance, pyrrolylalso includes 2H-pyrrolyl.

[0056] The Het radical may be attached to the remainder of the moleculeof formula (I) or (I-a) through any ring carbon or heteroatom asappropriate. Thus, for example, when the heterocycle is pyridinyl, itmay be 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

[0057] When any variable (eg. aryl, R², R⁶ etc.) occurs more than onetime in any constituent, each definition is independent.

[0058] Lines drawn into ring systems from substituents indicate that thebond may be attached to any of the suitable ring atoms.

[0059] It will be appreciated that some of the compounds of formula (I)or (I-a) and their N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

[0060] The term “stereochemically isomeric forms” as used hereinbeforedefines all the possible stereoisomeric forms which the compounds offormula (I) or (I-a), and their N-oxides, addition salts, quaternaryamines or physiologically functional derivatives may possess. Unlessotherwise mentioned or indicated, the chemical designation of compoundsdenotes the mixture of all possible stereochemically isomeric forms,said mixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) or (I-a) and their N-oxides, salts, solvates or quaternaryamines substantially free, i.e. associated with less than 10%,preferably less than 5%, in particular less than 2% and most preferablyless than 1% of the other isomers. In particular, stereogenic centersmay have the R- or S-configuration; substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an Eor Z-stereochemistry at said double bond. Stereochemically isomericforms of the compounds of formula (I) or (I-a) are obviously intended tobe embraced within the scope of this invention.

[0061] For therapeutic use, salts of the compounds of formula (I) or(I-a) are those wherein the counterion is pharmaceutically acceptable.However, salts of acids and bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound. All salts,whether pharmaceutically acceptable or not are included within the ambitof the present invention.

[0062] The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) or (I-a) are able to form. The pharmaceutically acceptableacid addition salts can conveniently be obtained by treating the baseform with such appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

[0063] Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

[0064] The compounds of formula (I) or (I-a) containing an acidic protonmay also be converted into their non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

[0065] The term addition salt as used hereinabove also comprises thesolvates which the compounds of formula (I) or (I-a) as well as thesalts thereof, are able to form. Such solvates are for example hydrates,alcoholates and the like.

[0066] Some of the compounds of formula (I) or (I-a) may also exist intheir tautomeric form. Such forms although not explicitly indicated inthe above formula are intended to be included within the scope of thepresent invention.

[0067] Whenever used hereinafter, the term “compounds of formula (I)” or“compounds of formula (I-a)” is meant to include also the N-oxides, theaddition salts, the quaternary amines and all stereoisomeric forms.

[0068] A special group of compounds contains those compounds of formula(I) wherein R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl.

[0069] Another special group of compounds contains those compounds offormula (I) wherein one or more of the following restrictions apply:

[0070] i) -a¹=a²-a³=a⁴- is a radical of formula (a-1);

[0071] ii) R¹ is hydrogen;

[0072] iii) n is 1;

[0073] iv) R² is cyano, preferably in the para position relative to the—NR¹— group;

[0074] v) Y is cyano, —C(═O)NH₂ or a halogen, preferably a halogen;

[0075] vi) Q is hydrogen or —NR⁴R⁵ wherein R⁴ and R⁵ are preferablyhydrogen;

[0076] vii) L is —X—R³ wherein X is preferably NR¹, O or S, mostpreferably X is NH, and R³ is substituted phenyl with C₁₋₆alkyl, halogenand cyano as preferred substituents.

[0077] Still another special group of compounds contains those compoundsof formula (I-a) wherein R¹ is hydrogen, aryl, formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxy-carbonly, C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl.

[0078] Another special group of compounds contains also those compoundsof formula (I-a) wherein one or more of the following restrictionsapply:

[0079] i) -b¹=b²-C(R^(2a))=b³-b⁴=is a radical of formula (b-1);

[0080] ii) q is 0;

[0081] iii) R^(2a) is cyano or —C(═O)NH₂, preferably R^(2a) is cyano;

[0082] iv) Y is cyano, —C(═O)NH₂ or a halogen, preferably a halogen;

[0083] v) Q is hydrogen or —NR⁴R⁵ wherein R⁴ and R⁵ are preferablyhydrogen;

[0084] vi) L is —X—R³ wherein X is preferably NR¹, O or S, mostpreferably X is NH, and R³ is substituted phenyl with C₁₋₆alkyl, halogenand cyano as preferred substituents.

[0085] An interesting group of compounds are those compounds of formula(I) or (I-a) wherein L is —X—R³ wherein R³ is 2,4,6-trisubstitutedphenyl, each substituent independently selected from chloro, bromo,fluoro, cyano or C₁₋₄alkyl.

[0086] Also interesting are those compounds of formula (I) or (I-a)wherein Y is chloro or bromo and Q is hydrogen or amino.

[0087] Particular compounds are those compounds of formula (I) or (I-a)wherein the moiety in the 2 position of the pyrimidine ring is a4-cyano-anilino group.

[0088] Preferred compounds are those compounds of formula (I) or (I-a)wherein the moiety in the 2 position of the pyrimidine ring is a4-cyano-anilino group, L is —X—R³ wherein R³ is a 2,4,6-trisubstitutedphenyl, Y is a halogen and Q is hydrogen or NH₂.

[0089] Most preferred compounds are:

[0090]4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;

[0091]4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;

[0092]4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;

[0093]4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;

[0094]4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;

[0095]4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;and

[0096]4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;theN-oxides, the addition salts, the quaternary amines and thestereochemically isomeric forms thereof.

[0097] In general, compounds of formula (I-a) can be prepared byreacting an intermediate of formula (II) wherein W¹ is a suitableleaving group such as, for example, a halogen, hydroxy, triflate,tosylate, thiomethyl, methylsulfonyl, trifluoromethylsulfonyl and thelike, with an amino derivative of formula (III) optionally undersolvent-free conditions or in a reaction-inert solvent such as, forexample, ethanol, 1-methyl-2,-pyrrolidinone, N,N-dimethylformamide,1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane,acetonitrile and the like, under a reaction-inert atmosphere such as,for example, oxygen free argon or nitrogen, and optionally in thepresence of an acid such as, for example, 1 N hydrochloric acid indiethyl ether or the like. This reaction can be performed at atemperature ranging between 50° C. and 250° C.

[0098] In this and the following preparations, the reaction products maybe isolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

[0099] The compounds of formula (I-a) wherein L is a radical of formula—NR¹—R³, said compounds being represented by formula (I-a-1), can beprepared by reacting an intermediate of formula (IV) wherein W² is asuitable leaving group such as, for example, a halogen or a triflate,with an intermediate of formula (V) under solvent-free conditions or inan appropriate solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of an acidsuch as, for example, 1 N hydrochloric acid in diethyl ether. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

[0100] The compounds of formula (I-a) wherein L is a radical of formula—O—R³, said compounds being represented by formula (I-a-2), can beprepared by reacting an intermediate of formula (IV) wherein W² is asuitable leaving group such as, for example a halogen or a triflate,with an intermediate of formula (VI) in an appropriate solvent such as,for example, 1,4-dioxane, dimethyl sulfoxide, tetraline, sulfolane andthe like under a reaction-inert atmosphere such as, for example, oxygenfree argon or nitrogen, and in the presence of a base such as, forexample, sodium hydride, potassium hydride, sodium hydroxide or thelike. This reaction can be performed at a temperature ranging between50° C. and 250° C.

[0101] The compounds of formula (I-a) may further be prepared byconverting compounds of formula (I-a) into each other according toart-known group transformation reactions.

[0102] The compounds of formula (I-a) may be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form. Said N-oxidationreaction may generally be carried out by reacting the starting materialof formula (I-a) with an appropriate organic or inorganic peroxide.Appropriate inorganic peroxides comprise, for example, hydrogenperoxide, alkali metal or earth alkaline metal peroxides, e.g. sodiumperoxide, potassium peroxide; appropriate organic peroxides may compriseperoxy acids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoicacid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

[0103] For instance, the compounds of formula (I-a) wherein Q is ahalogen may be converted to the corresponding compounds wherein Q is—NR⁴H using NH₂R⁴ as a reagent in a reaction inert solvent such as, forexample, 1,4-dioxane and the like, optionally in the presence of asuitable base such as, for example, triethylamine orN,N-diisopropylethylamine or the like. In case R⁴ contains a hydroxymoiety, it may be convenient to perform the above reaction with aprotected form of NH₂R⁴ whereby the hydroxy moiety bears a suitableprotecting group P being, for instance, a trialkylsilyl group, andsubsequently removing the protective group according to art-knownmethodologies.

[0104] Some of the compounds of formula (I-a) and some of theintermediates in the present invention may contain an asymmetric carbonatom. Pure stereochemically isomeric forms of said compounds and saidintermediates can be obtained by the application of art-knownprocedures. For example, diastereoisomers can be separated by physicalmethods such as selective crystallization or chromatographic techniques,e.g. counter current distribution, liquid chromatography and the likemethods. Enantiomers can be obtained from racemic mixtures by firstconverting said racemic mixtures with suitable resolving agents such as,for example, chiral acids, to mixtures of diastereomeric salts orcompounds; then physically separating said mixtures of diastereomericsalts or compounds by, for example, selective crystallization orchromatographic techniques, e.g. liquid chromatography and the likemethods; and finally converting said separated diastereomeric salts orcompounds into the corresponding enantiomers. Pure stereochemicallyisomeric forms may also be obtained from the pure stereochemicallyisomeric forms of the appropriate intermediates and starting materials,provided that the intervening reactions occur stereospecifically.

[0105] An alternative manner of separating the enantiomeric forms of thecompounds of formula (I-a) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

[0106] Some of the intermediates and starting materials are knowncompounds and may be commercially available or may be prepared accordingto art-known procedures.

[0107] Intermediates of formula (II) wherein L is —X—R³, saidintermediates being represented by formula (II-1) can be prepared byreacting a pyrimidine derivative of formula (VII) wherein each W¹ is asdefined previously, with HXR³ (VIII) in a reaction inert solvent suchas, for example, 1,4-dioxane, 2-propanol or the like, and in thepresence of a base such as, for example, triethylamine orN,N-diisopropylethylamine or the like. Different regio-specific isomersmay be formed and can be separated from one another using suitableseparation techniques such as, for example, chromatography.

[0108] Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (VII-a) wherein W² is a suitable leaving groupsuch as, for example, a halogen, with an intermediate of formula (IX) ina suitable solvent such as, for example, 1-methyl-2-pyrrolidinone,1,4-dioxane or the like, in the presence of an acid such as, forexample, 1 N hydrochloric acid in diethyl ether. This reaction can beperformed at a temperature ranging between 50° C. and 250° C.

[0109] Alternatively, intermediates of formula (IV) can be prepared byreacting an intermediate of formula (X) with phosphorous oxychloride,triflic anhydride or a functional derivative thereof under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen. This reaction can be performed at a temperature rangingbetween 20° C. and 150° C.

[0110] Intermediates of formula (X) can be prepared by reacting anintermediate of formula (XI) or a functional derivative thereof, with anintermediate of formula (IX). This reaction may be performed undersolvent-free conditions or in an appropriate solvent such as, forexample, diglyme, tetraline or the like under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen, andoptionally in the presence of a base such as, for example, sodiumhydride, potassium hydride or the like. This reaction can be performedat a temperature ranging between 100° C. and 250° C.

[0111] Intermediates of formula (X) can also be prepared by reacting anintermediate of formula (XII), wherein W² is a suitable leaving groupand Y and Q are as defined for a compound of formula (I-a), with anintermediate of formula (XIII) in an appropriate solvent such as , forexample, ethanol, or the like, and in the presence of a base such as,for example, sodium ethoxide or the like, under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen. Thereaction can be performed at a temperature ranging between 20° C. and125° C.

[0112] A convenient way of preparing an intermediate of formula (IV)wherein Y is a bromine or chloro atom, said intermediates beingrepresented by formula (IV-1), involves the introduction of a bromine orchloro atom to an intermediate of formula (XIV), wherein W² is aspreviously defined, using N-bromosuccinimide or N-chlorosuccinimide in areaction-inert solvent such as, for example, chloroform, carbontetrachloride or the like. This reaction can be performed at atemperature ranging between 20° C. and 125° C.

[0113] Analogous to the conversion of compounds of formula (I-a) whereinQ is a halogen to compounds of formula (I-a) wherein Q is —NHR⁴, theintermediates of formula (II), (IV) and (VII) can also be converted.

[0114] The compounds of formula (I-a) as prepared in the hereinabovedescribed processes may be synthesized as a mixture of stereoisomericforms, in particular in the form of racemic mixtures of enantiomerswhich can be separated from one another following art-known resolutionprocedures. The racemic compounds of formula (I-a) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I-a)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

[0115] It will be appreciated by those skilled in the art that in theprocesses described above the functional groups of intermediatecompounds may need to be blocked by protecting groups.

[0116] Functional groups which it is desirable to protect includehydroxy, amino and carboxylic acid. Suitable protecting groups forhydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

[0117] The protection and deprotection of functional groups may takeplace before or after a reaction step.

[0118] The use of protecting groups is fully described in ‘ProtectiveGroups in Organic Chemistry’, edited by J W F McOmie, Plenum Press(1973), and ‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T WGreene & P G M Wutz, Wiley Interscience (1991).

[0119] The compounds of formula (I) and (I-a) show antiretroviralproperties, in particular against Human Immunodeficiency Virus (HIV),which is the aetiological agent of Acquired Immune Deficiency Syndrome(AIDS) in humans. The HIV virus preferentially infects human T-4 cellsand destroys them or changes their normal function, particularly thecoordination of the immune system. As a result, an infected patient hasan everdecreasing number of T-4 cells, which moreover behave abnormally.Hence, the immunological defense system is unable to combat infectionsand neoplasms and the HIV infected subject usually dies by opportunisticinfections such as pneumonia, or by cancers. Other conditions associatedwith HIV infection include thrombocytopaenia, Kaposi's sarcoma andinfection of the central nervous system characterized by progressivedemyelination, resulting in dementia and symptoms such as, progressivedysarthria, ataxia and disorientation. HIV infection further has alsobeen associated with peripheral neuropathy, progressive generalizedlymphadenopathy (PGL) and AIDS-related complex (ARC).

[0120] The present compounds also show activity against HIV-1 strainsthat have acquired resistance to art-known non-nucleoside reversetranscriptase inhibitors. They also have little or no binding affinityto human α-1 acid glycoprotein.

[0121] Due to their antiretroviral properties, particularly theiranti-HIV properties, especially their anti-HIV-1-activity, the compoundsof formula (I) or (I-a), their N-oxides, pharmaceutically acceptableaddition salts, quaternary amines and stereochemically isomeric formsthereof, are useful in the treatment of individuals infected by HIV andfor the prophylaxis of these infections. In general, the compounds ofthe present invention may be useful in the treatment of warm-bloodedanimals infected with viruses whose existence is mediated by, or dependsupon, the enzyme reverse transcriptase. Conditions which may beprevented or treated with the compounds of the present invention,especially conditions associated with HIV and other pathogenicretroviruses, include AIDS, AIDS-related complex (ARC), progressivegeneralized lymphadenopathy (PGL), as well as chronic CNS diseasescaused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

[0122] The compounds of the present invention or any subgroup thereofmay therefore be used as medicines against above-mentioned conditions.Said use as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1.

[0123] The compounds of the present invention or any subgroup thereofmay be formulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0124] To aid solubility of the compounds of formula (I-a), suitableingredients, e.g. cyclodextrins, may be included in the compositions.Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers andmixed ethers thereof wherein one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

[0125] The term mixed ether denotes cyclodextrin derivatives wherein atleast two cyclodextrin hydroxy groups are etherified with differentgroups such as, for example, hydroxy-propyl and hydroxyethyl.

[0126] The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

[0127] Other suitable compositions for oral or rectal administrationcomprise particles obtainable by melt-extruding a mixture comprising acompound of formula (I-a) and an appropriate water-soluble polymer andsubsequently milling said melt-extruded mixture. Said particles can thenbe formulated by conventional techniques into pharmaceutical dosageforms such as tablets and capsules.

[0128] Said particles consist of a solid dispersion comprising acompound of formula (I-a) and one or more pharmaceutically acceptablewater-soluble polymers. The preferred technique for preparing soliddispersions is the melt-extrusion process comprising the followingsteps:

[0129] a) mixing a compound of formula (I-a) and an appropriatewater-soluble polymer,

[0130] b) optionally blending additives with the thus obtained mixture,

[0131] c) heating the thus obtained blend until one obtains a homogenousmelt,

[0132] d) forcing the thus obtained melt through one or more nozzles;and

[0133] e) cooling the melt till it solidifies.

[0134] The solid dispersion product is milled or ground to particleshaving a particle size of less than 1500 μm, preferably less than 400μm, more preferably less than 250 μm and most preferably less than 125μm.

[0135] The water-soluble polymers in the particles are polymers thathave an apparent viscosity, when dissolved at 20° C. in an aqueoussolution at 2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitablewater-soluble polymers include alkylcelluloses, hydroxyalkyl-celluloses,hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal saltsof carboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates,polysaccharides, polyacrylic acids and the salts thereof,polymethacrylic acids and the salts and esters thereof, methacrylatecopolymers, polyvinylalcohol, polyalkylene oxides and copolymers ofethylene oxide and propylene oxide. Preferred water-soluble polymers areEudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.

[0136] Also one or more cyclodextrins can be used as water solublepolymer in the preparation of the above-mentioned particles as isdisclosed in WO 97/18839. Said cyclodextrins include thepharmaceutically acceptable unsubstituted and substituted cyclodextrinsknown in the art, more particularly α, β or γ cyclodextrins or thepharmaceutically acceptable derivatives thereof.

[0137] Substituted cyclodextrins which can be used include polyethersdescribed in U.S. Pat. No. 3,459,731. Further substituted cyclodextrinsare ethers wherein the hydrogen of one or more cyclodextrin hydroxygroups is replaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₁₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl orcarboxyethyl.

[0138] Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-βcyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

[0139] A more novel type of substituted cyclodextrins issulfobutylcyclodextrines.

[0140] The ratio of the compound of formula (I-a) over cyclodextrin mayvary widely. For example ratios of 1/100 to 100/1 may be applied.Interesting ratios of the compound of formula (I-a) over cyclodextrinrange from about 1/10 to 10/1. More interesting ratios range from about1/5 to 5/1.

[0141] It may further be convenient to formulate the compounds offormula (I-a) in the form of nanoparticles which have a surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than 1000 nm. Useful surfacemodifiers are believed to include those which physically adhere to thesurface of the compound of formula (I-a) but do not chemically bond tosaid compound.

[0142] Suitable surface modifiers can preferably be selected from knownorganic and inorganic pharmaceutical excipients. Such excipients includevarious polymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

[0143] Yet another interesting way of formulating the compounds offormula (I-a) involves a pharmaceutical composition whereby thecompounds of formula (I-a) are incorporated in hydrophilic polymers andapplying this mixture as a coat film over many small beads, thusyielding a composition which can conveniently be manufactured and whichis suitable for preparing pharmaceutical dosage forms for oraladministration.

[0144] Said beads comprise a central, rounded or spherical core, acoating film of a hydrophilic polymer and a compound of formula (I-a)and a seal-coating polymer layer.

[0145] Materials suitable for use as cores in the beads are manifold,provided that said materials are pharmaceutically acceptable and haveappropriate dimensions and firmness. Examples of such materials arepolymers, inorganic substances, organic substances, and saccharides andderivatives thereof.

[0146] It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

[0147] Those of skill in the treatment of HIV-infection could determinethe effective daily amount from the test results presented here. Ingeneral it is contemplated that an effective daily amount would be from0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

[0148] The exact dosage and frequency of administration depends on theparticular compound of formula (I) or (I-a) used, the particularcondition being treated, the severity of the condition being treated,the age, weight and general physical condition of the particular patientas well as other medication the individual may be taking, as is wellknown to those skilled in the art. Furthermore, it is evident that saideffective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines and are not intended to limit the scope or use of theinvention to any extent.

[0149] Also, the combination of an antiretroviral compound and acompound of formula (I) or (I-a) can be used as a medicine. Thus, thepresent invention also relates to a product containing (a) a compound offormula (I) or (I-a), and (b) another antiretroviral compound, as acombined preparation for simultaneous, separate or sequential use inanti-HIV treatment. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers. Saidother antiretroviral compounds may be known antiretroviral compoundssuch as nucleoside reverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI),zalcitabine (dideoxycytidine, ddC) or lamivudine(3′-thia-2′-3′-dideoxycytidine, 3TC) and the like; non-nucleosidereverse transciptase inhibitors such as suramine, pentamidine,thymopentin, castanospermine, efavirenz, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and thelike; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitro-phenyl)amino]-2,6-dichlorobenzene-acetamide and the like;TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g.indinavir, ritanovir, saquinovir, ABT-378 and the like; orimmunomodulating agents, e.g. levamisole and the like. The compound offormula (I) or (I-a) can also be combined with another compound offormula (I) or (I-a).

[0150] The following examples are intended to illustrate the presentinvention.

[0151] Experimental Part

[0152] A. Preparation of the Intermediate Compounds

EXAMPLE A1

[0153] Reaction under argon atmosphere. A solution of2,4,6-trimethylbenzenamine (0.00461 mol) in 1,4-dioxane (5 ml) was addedto a solution of 5-bromo-2,4-dichloropyrimidine (0.00439 mol) in1,4-dioxane (5 ml). N,N-bis(1-methylethyl)ethanamine (0.00548 mol) wasadded. The reaction mixture was stirred and refluxed for 20 hours. Thesolvent was evaporated. The residue was dissolved in ethyl acetate,washed with a saturated aqueous sodium bicarbonate solution, water andbrine, dried with sodium sulfate, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: 1:5, 1:2 and 1:1 CH₂Cl₂: hexane). Two pure fractiongroups were collected and their solvent was evaporated, yielding 0.35 g(24%) of 5-bromo-4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine(interm. 1) and 0.93 g (65%) of5-bromo-2-chloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine (interm. 2).

EXAMPLE A2

[0154] a) 4-Hydroxy-5-chloro-2-methylthiopyrimidine (0.0156 mol) and4-aminobenzonitrile (0.078-mol) were combined as a melt and stirred at180-200° C. for 6 hours. The reaction mixture was cooled, and trituratedsequentially with boiling CH₂Cl₂ and CH₃CN to obtain 95% pure compound,which was dried, yielding 1.27 g (33%) of4-[(5-chloro-4-hydroxy-2-pyrimidinyl)amino]benzonitrile (interm. 3;mp. >300° C.).

[0155] b) POCl₃ (10 ml) was added to intermediate (3) (0.0028 mol). Theflask was equipped with a condenser and heated to 80° C. for 35 minutes.The material was quenched on ice and allowed and the resultingprecipitate was collected and washed with water (50 ml). The sample wasdried. A fraction thereof was further purified by columnchromato-graphy. The pure fractions were collected and the solvent wasevaporated, yielding 4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrile(interm. 4).

[0156] c) The mixture of intermediate (4) (0.0132 mol) intetrahydrofuran (75 ml) and CH₂Cl₂ (10 ml) was stirred for 15 min. HClin diethyl ether (0.0145 mol) was added slowly, and the mixture wasstirred for 5 minutes. The solvent was removed under reduced pressure,yielding 3.98 g of 4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrilemonohydrochloride (interm. 5).

EXAMPLE A3

[0157] a)2,4,5,6-tetrachloropyrimidine (0.0134 mol), 1,4-dioxane (30ml), 2,4,6-trimethyl aniline (0.0134 mol), andN,N-bis(1-methylethyl)ethanamine (0.0136 mol) were added to a flaskunder argon and stirred at 55° C. for 16 hours. The solvent wasevaporated, and the residue was dissolved in CH₂Cl₂, then purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/hexane ¼, and ½).The desired fractions were collected and their solvent was evaporated,yielding 0.15 g4,5,6-trichloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 6)and 3.15 g 2,5,6-trichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine(interm. 7).

[0158] b) A mixture of intermediate 7 (0.00474 mol) in NH₃, (2.0 M in2-propanol; 20 ml) was heated in a pressure vessel at 75-80° C. for 40hours. The temperature was increased to 110-115° C. The solvent wasevaporated to produce 1.85 g of residue. The sample was heated with NH₃,(0.5 M in 1,4-dioxane; 20 ml) at 125° C. for 18 hours. The solvent wasevaporated, yielding 1.7 g of a mixture of two isomers, i.e.2,5-dichloro-N4-(2,4,6-trimethylphenyl)-4,6-pyrimidinediamine (interm.8) and 5,6-dichloro-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine(interm. 9).

EXAMPLE A4

[0159] a) A mixture of4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile, (0.12 mol) inPOCl₃ (90 ml) was stirred and refluxed under Argon for 20 minutes. Thereaction mixture was slowly poured onto 750 ml ice/water, and the solidwas separated by filtration. The solid was suspended in 500 ml water,and the pH of the suspension was adjusted to neutral by adding a 20%NaOH solution. The solid was again separated by filtration, suspended in200 ml 2-propanone, and 1000 ml CH₂Cl₂ was added. The mixture was heateduntil all solid had dissolved. After cooling to room temperature, theaqueous layer was separated, and the organic layer was dried. Duringremoval of the drying agent by filtration, a white solid formed in thefiltrate. Further cooling of the filtrate in the freezer, followed byfiltration, yielded 21.38 g (77.2%) of4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 10).

[0160] b) Intermediate (10) (0.005 mol), 1-bromo-2,5-pyrrolidinedione(0.006 mol) and trichloromethane (10 ml) were combined in a sealed tubeand heated at 100° C. overnight. The reaction mixture was allowed tocool to room temperature. Silica gel (2 g) was added, and the solventwas evaporated. The residue was purified by flash column chromatographyover silica gel (eluent: CH₂Cl₂/hexanes 9/1). The pure fractions werecollected and the solvent was evaporated, yielding 1.31 g (84.5%) of4-[(5-bromo-4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 11).

EXAMPLE A5

[0161] To a flask under Argon was added4-amino-2,5,6-trichloropyrimidine (0.08564 mol), 4-amino-benzonitrile(0.1071 mol), 1-methyl-2-pyrrolidinone (17 ml) and HCl in diethylether(1M; 85.6 ml). The mixture was placed in an oil bath at 130° C. under astream of nitrogen until the ether was gone. An additional 10 ml of1-methyl-2-pyrrolidinone was added. The mixture was heated at 145° C.for 16 hours under argon. 1,4-Dioxane was added. The mixture wasrefluxed, cooled, then filtered. The filtrate was evaporated. Theresidue was dissolved in CH₂Cl₂, washed with 1 N NaOH, then filtered.The solid was dissolved in 2-propanone, evaporated onto silica gel, andchromatographed using 1-3% 2-propanone in hexane as eluent. The purefractions were collected and the solvent was evaporated, yielding 1.63 g(6.8%) of 4-[(4-amino-5,6-dichloro-2-pyrimidinyl)amino]benzonitrile(interm. 12).

[0162] B. Preparation of the Final Compounds

EXAMPLE B1

[0163] a) To a flask under argon containing intermediate (1) (0.00107mol) was added ether. To this homogeneous solution was addedHCl/diethylether (1M; 0.00109 mol). The solvent was evaporated and1,4-dioxane (35 ml) and 4-aminobenzonitrile (0.00322 mol) were added.The reaction mixture was stirred and refluxed for 4 days. The solventwas evaporated. The residue was dissolved in CH₂Cl₂, washed with asaturated sodium bicarbonate solution, dried, filtered and the solventwas evaporated to give 0.79 g of amber oil. The oil was purified byreverse phase HPLC. The desired fractions were collected and the solventwas evaporated, yielding residues 1 and 2. Residue 1 was purified bycolumn chromatography over silica gel (eluent: 0 and 2% CH₃OH:CH₂Cl₂).The pure fractions were collected and the solvent was evaporated,yielding 0.0079 g (2.0%) of4-[[5-chloro-2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile(compound 1). Residue 2 was purified by column chromatography oversilica gel (eluent: 0 and 2% CH₃OH:CH₂Cl₂). The pure fractions werecollected and the solvent was evaporated, yielding 0.0044 g (1.0%) of4-[[5-bromo-2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile(compound 2).

[0164] b) To a flask containing intermediate 2 (0.00285 mol) was addedether. To this homogeneous solution was added HCl in diethyl ether (1M;0.00855 mol). The solvent was evaporated and 1,4-dioxane (20 ml) wasadded. Finally, 4-aminobenzonitrile (0.00291 mol) and 1,4-dioxane (15ml) were added and the reaction mixture was stirred and refluxed forseven days. The solvent was evaporated, the residue dissolved in CH₂Cl₂,washed with 1 M NaOH, and the solvent evaporated. The residue wasdissolved in CH₂Cl₂ (10 ml) and the precipitate was filtered off anddried, yielding 0.15 g (13%) of4-[[5-bromo-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 3).

EXAMPLE B2

[0165] a) A 3:1 mixture of intermediate (8) and intermediate (9) [asprepared in example A3b] and 4-aminobenzonitrile (0.01422 mol) washeated in a pressure vessel at 180° C. for 5 hours. The sample waspartitioned between CH₂Cl₂ and diluted NaHCO₃, dried over K₂CO₃,filtered, and evaporated. CH₃CN was stirred in, the resultingprecipitate removed by filtration. The filtrate was further purified byreverse phase HPLC. The pure fractions were collected and the solventwas evaporated, yielding 0.17 g of4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitriletrifluoroacetate (1:1) (comp. 4).

EXAMPLE B3

[0166] HCl in diethylether (1M; 0.0045 mol) was added to a suspension ofintermediate (4) (0.003 mol) in 1,4-dioxane (5 ml), stirred under argonin a sealable tube. The mixture was warmed to evaporate thediethylether, and 2,4,6-trimethylbenzenamine (0.009 mol) was added. Thetube was sealed, and the reaction mixture was heated to 150° C. for 12hours. The reaction mixture was allowed to cool to room temperature.Sequentially, silica gel (2.2 g) and CH₃OH (50 ml) were added. Afterevaporating the solvent, the residue was purified by flashchromatography (eluent gradient: CH₂Cl₂:CH₃OH: NH4OH 99.5:0.45:0.05 upto 99:0.9:0.1). The pure fractions were collected and the solvent wasevaporated. The residue was dried, yielding 0.80 g (73.4%) of4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 5).

EXAMPLE B4

[0167] A mixture of intermediate (5) (0.0025 mol) and2,6-dibromo-4-methylbenzenamine (0.0075 mol) in 1,3-dioxane (5.0 ml) ina sealed tube under argon was heated and stirred at 160° C. for 16hours. The reaction mixture was concentrated by rotary evaporation ontosilica gel (2.0 g). The material was purified by flash chromatography(eluent 1:1 hexanes: CH₂Cl₂; neat CH₂Cl₂; 0.5%, 1% (10% NH₄OH in CH₃OH)in CH₂Cl₂) for 90% purity. Recrystallization afforded 0.15 g (12.2%) of4-[[5-chloro-4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 10; 95% purity).

EXAMPLE B5

[0168] NaH (0.0075 mol; 60% suspension in oil) was added to a suspensionof 2,4,6-trimethyl-phenol (0.0075 mol) in 1,4-dioxane (5 ml) in asealable tube under argon. The mixture was stirred for 15 minutes, andintermediate (4) (0.0025 mol) was added. The tube was sealed, and thereaction mixture was heated to 150° C. for 15 hours. The reaction wasallowed to cool to room temperature. After silica gel (2.0 g) was added,the solvent was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent gradient: CH₂Cl₂:hexanes 9:1 upto 100:0; then CH₂Cl₂:CH₃OH:NH₄OH 100:0:0 up to 97:2.7:0.3). The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding 0.73 g of (80.2%)4-[[5-chloro-4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (comp. 6).

EXAMPLE B6

[0169] a) NaH, 60% suspension in oil (0.003 mol) and1-methyl-2-pyrrolidinone (3 ml) were added to a suspension of4-hydroxy-3,5-dimethylbenzonitrile (0.003 mol) in 1,4-dioxane (3 ml) ina sealable tube under argon. After the H₂ had evolved, intermediate (11)(0.001 mol) was added. The tube was sealed and the reaction mixture washeated to 160° C. for 16 hours. The mixture was cooled to roomtemperature, transferred to a beaker and diluted with methanol (20 ml).Water (200 ml) was added dropwise. The aqueous mixture was extractedwith CH₂Cl₂/CH₃OH 90/10 (3×300 ml). The organic layer was separated,dried, filtered and adsorbed onto silica gel (1 g). The solvent wasevaporated and the residue was purified by flash column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH from 100/0/0 to 98/1.8/0.2).The desired fractions were collected and the solvent was evaporated. Theresidue was triturated with hot CH₃CN, filtered off, then dried,yielding 0.20 g (47.6%) of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(comp. 17).

[0170] b) n-Butyllithium (0.010 mol) was added to a solution ofN-(1-methylethyl)-2-propanamine (0.010 mol) in tetrahydrofuran (250 ml),stirred at 0° C. After stirring cold for 30 min, compound (17) (0.005mol) was added. The resulting mixture was stirred cold for 15 min atwhich point ethyl 2-bromoethanoate (0.015 mol) was added and thetemperature was allowed to rise to room temperature and the reactionmixture was stirred for 16 hours which drove the reaction to 50%completion. Quenched with 0.5 ml H₂O, the sample was concentrated byrotary evaporation onto silica gel, and purified by flash chromatography(Biotage Flash 40M, eluting with 0, 0.5, 1% (10% NH₄OH in CH₃OH) inCH₂Cl₂) to give a white solid which was 1:1 starting material A:product.Preparatory HPLC purification eluting into tubes containing 1 mmolNaHCO₃ effected final purification. Lyophilized material was taken up inwater/CH₂Cl₂ (1:1 (50 ml total)) and separated. The aqueous phase wasextracted 2 more times with 25 ml CH₂Cl₂. The organic layers werecombined and dried over sodium sulfate, filtered and rotary evaporatedto white solid dried in vacuo at 65° C. 18 hours. Yield: 0.33 g of

[0171] (13%, white solid); mp. 185-190° C. (comp. 59).

[0172] c) Reaction under Ar flow. NaH 60% (0.00600 mol) was stirred intetrahydrofuran (20 ml). Compound (17) (0.00476 mol) was added and themixture was stirred for 15 min. Chloromethyl-2,2-dimethylpropanoate(0.00600 mol) was added and the reaction mixture was stirred for 16hours at room temperature, then stirred and refluxed for 4.5 hours, thencooled. Tetrahydrofuran (20 ml) was added. NaH 60% (0.00600 mol) andchloromethyl-2,2-dimethylpropanoate (0.00600 mol) were added and theresulting reaction mixture was stirred for 24 hours. The solvent wasevaporated. The residue was dissolved in CH₂Cl₂, washed with water, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 and99.5/0.5). The desired fractions were collected and the solvent wasevaporated. The residue was purified on the Gilson. This fraction wascrystallized from 2-propanol, filtered off and dried. Yield: 0.60 g of

[0173] (23.6%, white solid) (comp. 60).

[0174] d) A suspension of compound (17) (0.0020 mol) in tetrahydrofuran(40 ml) was treated with 0.24 g of NaH in one portion. The effervescentmixture was stirred for 2 hours to afford a bright yellow suspension. Asolution of 2,2′-oxybisacetyl chloride (0.020 mol) in tetrahydrofuran(10 ml) was prepared and cooled in an ice bath. Via cannula, theresultant A/B suspension was transferred to the cold solution of2,2′-oxybisacetyl chloride dropwise over 10 minutes. The mixture waswarmed to room temperature and stirred for 3 days. Another 0.24 g of NaHwas added and after 2 days the reaction was cooled in an ice bath andtreated with a mixture of methanol (0.150 mol) and N,N-diethylethanamine(0.150 mol) dropwise over 30 minutes. The reaction mixture was warmed toroom temperature and after 16 hours poured into ether and extracted withsaturated NaHCO₃. The aqueous fraction was extracted 2× with ether andthe combined ether extracts were backwashed 3× with water and dried overMgSO₄. Concentration afforded 2.91 g of an oily residue that wassubjected to reverse phase prep HPLC. Lyophilization of the appropriatefractions provided 0.16 g of the

[0175] sample as a beige powder (14.5% purified yield) (comp. 61).

EXAMPLE B7

[0176] To a pressure vessel under argon was added intermediate 12(0.00286 mol), 4-cyano-2,6-dimethylaniline (0.00571 mol), 1M HCl indiethyl ether (0.00140 mol) and 1,4-dioxane (8 ml). The reaction mixturewas heated in an oil bath under a stream of nitrogen until all thesolvents had evaporated. 1-methyl-2-pyrrolidinone (3 ml) was added, andthe reaction mixture heated at 220-240° C. for 3 hours. Heating wascontinued at 210-220° C. for 6 hours. The residue was dissolved in1,4-dioxane, evaporated, partitioned between CH₂Cl₂ and 1 N NaOH,filtered, dried organic layers with potassium carbonate and evaporated.The desired compound was isolated and purified by preparative reversephase chromatography. The pure fractions were collected and the solventwas evaporated, yielding 0.0165 g (1.1% after lyophilization) of4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitriletrifluoroacetate (1:1) (comp. 19).

EXAMPLE B8

[0177] A mixture of intermediate (11) (0.0011 mol),2,6-dimethyl-4-(2-propyl)benzenamine (0.0011 mol),N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.0022 mol) and 1 M HCl inether (2.3 ml) (0.0023 mol) in 1,4-dioxane (25 ml) was stirred andheated to 95° C. for 16 hours. Solvent was removed by rotary evaporationand the residue was purified by reverse phase preparatory HPLC. Thecombined fractions containing the desired material were lyophilized toyield 0.23 g of

[0178] (48%); mp. 198-201° C. (comp. 40)

EXAMPLE B9

[0179] N,N-di(methylethyl)ethanamine (0.0024 mol) was added to4-amino-2,5-dimethyl-3,4-benzonitrile (0.00219 mol) and4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]-benzonitrile (0.00218mol). The reaction vial was sealed and heated to 155-160° C. withstirring for 1.5 days. The sample was cooled to room temperature. Thesample was treated with flash column chromatography over silica gel(eluent: CH₂Cl₂). Purification was completed through preparative HPLC toyield 0.05 g of4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(5.0%); mp. 259-260° C. (comp. 42).

EXAMPLE B10

[0180] Sequentially 2,4,6-trimethylbenzenamine (0.0022 mol) andN,N-di(methylethyl)-ethanamine (0.0024 mol) were added to a solution ofand 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (0.00218mol) in 1,4-dioxane (10 ml). The tube was sealed and the suspension washeated to 120-130° C. in an oil bath while stirring for 90 hours. Themixture was cooled to room temperature. MoreN,N-di(methylethyl)-ethanamine (15 ml) was added, and the sample wasreheated to 120-130° C. for 64 hours. The reaction was heated at 150° C.for 6 days. The sample was cooled to room temperature. The sample wasdiluted with ethylacetate and extracted with cold 1M NaOH. The aqueousphase was backwashed with ethylacetate. The combined organic phases weredried and concentrated. Flash column chromatography over silica gel(eluent: CH₂Cl₂). The sample was further purified by preparatory HPLC toyield 0.53 g of4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile(54.9%); mp. 220-221° C. (comp. 41).

EXAMPLE B11

[0181] A mixture of 4-aminobenzonitrile (0.0043 mol) and

[0182] (0.0021 mol) in 1,4-dioxane (30 ml) was stirred at 100° C. for 16hours. The solvent was removed by rotary evaporation. The solid residuewas triturated and the residue was dried in vacuo at 40° C. for 16hours, yielding 0.452 g of

[0183] (55%); mp. >300° C. (comp. 43).

EXAMPLE B12

[0184] To a pressure vessel was added

[0185] (0.00567 mol),

[0186] 4-aminobenzonitrile (0.01163 mol) and 1-methyl-2-pyrrolidinone(20 ml). The reaction mixture was heated at 140° C. for 16 hours. Thereaction mixture was cooled to room temperature and acetonitrile andwater were added. The resulting precipitate was filtered, and the solidrecrystallized with acetonitrile to give 1.27 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-methyl-2-pyrimidinyl]amino]benzonitrile(52); mp. 260-262° C. (comp. 44).

EXAMPLE B13

[0187] Intermediate (11) (0.001 mol) and2,6-dimethyl-4-aminobenzonitrile (0.00473 mol) were combined and heatedto 150° C. while stirring for 16 hours. The sample was dissolved inCH₃OH and evaporated onto silica gel (1 g) and eluted with 1:1 hexanes:CH₂Cl₂, 4:1 CH₂Cl₂:hexanes, and neat CH₂Cl₂ (2 L). The desired fractionswere evaporated and the residue was dried in vacuo for 16 hours at 45°C. The thus obtained was transferred to a 4 ml vial in CH₂Cl₂ and thesolvent was evaporated, yielding 0.120 g of4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile(28.6%); mp. 277-280° C. (comp. 45).

EXAMPLE B14

[0188]4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile(0.00250 mol) and NH₃/1,4-dioxane 0.5M (0.015 mol) were heated in apressure vessel at 150° C. for 4 days. The sample was allowed to sit atambient conditions for 2 days. Water was added slowly to the mixtureuntil a precipitate formed. The mixture was stirred for 2 hours andfiltered. The solid was recrystallized from CH₃CN to obtain 0.58 g(fraction 1). The filtrate was evaporated (fraction 2). Both fractionswere combined and purified by column chromatography, eluting withCH₂Cl₂. The resulting residue of the desired fraction was recrystallizedfrom CH₃CN to yield 0.44 g of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]-amino]benzonitrile(40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (comp.46).

EXAMPLE B15

[0189]4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile(0.000660 mol), tetrahydrofuran (1 ml), and 1-pyrrolidineethanamine(0.00198 mol) were added to a pressure vessel. The mixture was heated at75° C. for 16 hours. CH₂Cl₂ was added, and the mixture was washed withwater, dried, filtered and the filtrate was evaporated. Purificationusing flash column chromatography eluting with 1:9 methanol:methylenechloride produced a solid which was redissolved in CH₃CN.HCl/diethylether 1.0M (0.48 ml) was added, and the mixture was cooled inice. Filtration yielded 0.19 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-[(1-pyrrolidinyl)ethylamino]-2-pyrimidinyl]amino]benzonitrilehydrochloride (1:1) (50.6%); mp. 208-210° C. (comp. 47).

EXAMPLE B16

[0190] To a pressure vessel was added4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile(0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g),tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture wasstirred for 3 days at room temperature, then for 1 day at 75° C., for 1day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). Theliquid was decanted into the reaction flask and the reaction mixture washeated at 110° C. for 3 days. The solvent was evaporated. The residuewas dissolved in CH₂Cl₂, washed with a saturated NaHCO₃ solution andwater, dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃CN, filtered offand dried, yielding 0.15 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]-benzonitrile(51%); mp. 185-186° C. The sample was dried (0.2 mm Hg, 80° C., 16hours) (comp. 48).

EXAMPLE B17

[0191] a) n-Butyllithium (2.0 1, 0.005 mol) was added to a 0° C. stirredsolution of 1-(methyl-ethyl)-2-propanamine (0.70 ml, 0.005 mol) andtetrahydrofuran (300 ml). After stirring cold for 30 min, compound (17)(0.005 mol) was added. The resulting mixture was stirred cold for 30 minat which point 1,1-dimethylethyl bromoacetate (1.5 ml, 10 mmol) wasadded and the temperature was allowed to rise to room temperature andthe reaction was stirred for three. In a separate flask n-butyllithium(2.0 ml, 5 mmol) was added to a stirred 0° C. solution of1-(methylethyl)-2-propanamine (0.70 ml, 5 mmol) in tetrahydrofuran (50ml) and allowed to react for 30 min at which time it was transferred tothe room temperature reaction. This procedure was repeated. Quenchedwith 0.5 ml H₂O, the sample was concentrated by rotary evaporation ontosilica gel, and purified by flash chromatography (eluting with 0, 10,20% ethylacetate in hexanes) to give a white solid of

[0192] mp. 195-197° C. (comp. 56).

[0193] b) A suspension of compound (17) in 40 ml ofN,N-dimethylformamide was treated with 0.24 g of NaH. The effervescentmixture was stirred for 90. A solution of 1,4-dichloro-1,4-butanedionein 10 ml N,N-dimethylformamide was prepared and cooled in an ice bath.The mixture prepared from compound (17) was transferred to the coldsolution of 1(methylethyl)-1-propanamine and was warmed to roomtemperature with stirring for 42 hours. Another 0.24 g of NaH was added,the reaction was stirred for 3 days, and diluted with ether and pouredinto ice. Precipitation was removed by filtration. The 2 phase filtratewas separated and the acidic aqueous fraction was extracted twice morewith ether. The combined ether fractions were washed with small volumesof distilled water and dried. The solvent was evaporated and the residuewas subjected to silica gel column chromatography. Reverse phase prepHPLC with immediate cooling for lyophilization of the appropriatefractions provided 0.07 g of

[0194] (7.8%); mp. 232-233° C. (comp. 57).

[0195] c) To a flask under argon was added NaH 60% and tetrahydrofuran.The reaction was stirred at room temperature for 10 min and compound(17) added. After stirring for 1 hr ethyl carbonochloridate was added.The reaction mixture was stirred at room temperature for another 16 hrsand the solvent evaporated. The residue was partially dissolved indimethylsulfoxide and filtered. The filtrate was purified by reversephase chromatography and lyophilized to give 0.47 g (18%) of

[0196] (comp. 58).

[0197] d) A mixture of of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile(0.00147 mol) in ethanoic acid anhydride (10 ml) and 2-propanone (10 ml)was stirred at room temperature for 16 hours. The mixture was thenheated to 55° C., and more ethanoic acid anhydride (3 ml) was added. Themixture was removed from heat after 18 hours and stirred for 6 days atroom temperature. The sample was concentrated by rotary evaporation to asolid. Purification by column chromatography (eluting with 0, 0.5, 1,1.5, 2% (10% NH₄OH in CH₃OH) in methylene chloride) yielded

[0198] mp. 290-295° C. The solid was dried in vacuo for 16 hours at 60°C. (comp. 49).

EXAMPLE B18

[0199] A mixture of4-[[4-(4-cyano-2,6-dimethylphenoxy)-5-nitro-2-pyrimidinyl]amino]-benzonitrile(0.0005 mol) in tetrahydrofuran (20 ml) was hydrogenated overnight withPd/C 10% (0.100 g) as a catalyst. After uptake of H₂ (3 equiv; 0.0015mol), the catalyst was filtered off and the filtrate was concentrated byrotary evaporation and dried in vacuo over 16 hours at 40° C., yielding0.15 g of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(84%); mp. >300° C. (comp. 50).

EXAMPLE B19

[0200]4-[[4-[(2,4,6-trimethylphenyl)amino]-5-nitro-2-pyrimidinyl]amino]benzonitrile(0.001 mol), Pd/C 10% (0.025 g), ethanol (20 ml), and hydrazine (0.030mol) were combined to form a slurry and stirred at room temperature for16 hours. The solvent was removed by rotary evaporation. The residue wastaken up in tetrahydrofuran (20 ml) and methanol (1 ml). A secondportion of hydrazine (0.5 g) was added, and the reaction was stirred for16 hours at room temperature. A third portion of hydrazine (0.5 ml) wasadded and the reaction was stirred for an additional 16 hours at roomtemperature. The sample was concentrated by rotary evaporation ontosilica gel (1 g) and purified by flash chromatography (eluent: 0.5, 1,2%10% (NH₄OH in CH₃OH) in CH₂Cl₂). The desired fractions were purified bypreparatory HPLC to yield 0.24 g of4-[[5-amino-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(70%); mp. 224-225° C. (comp. 51).

EXAMPLE B20

[0201] Compound (3) (0.001 mol), trimethyl silanecarbonitrile (0.0012mol), Pd(PPh₃)₂Cl₂ (0.020 g), CuI (0.010 g) and CF₃COOH/H₂O (3 ml) werecombined in a sealed tube and heated to 110° C. for 10 hours. Secondportions of the catalysts Pd(PPh₃)₂Cl₂ (0.020 g) and CuI (0.010 g), andCF₃COOH/H₂O (3 ml) were added and the reaction mixture was stirred for10 hours at 110° C. The material was concentrated by rotary evaporation.The residue was purified by preparative reversed-phase HPLC. The desiredfractions were concentrated and purified by reversed-phase preparativeHPLC and dried with a stream of N₂, then in vacuo at 40° C. for 16hours. Yield: 0.011 g of4-[[5-ethynyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 165-175° C. (comp. 52).

EXAMPLE B21

[0202] Compound (3) (0.000906 mol), tributylphenyl stannane (0.000906mol), Pd(PPh₃)₄ (0.002718 mol), and 1,4-dioxane (3 ml) were combinedunder N₂ in a sealed tube and heated to 110° C. for 16 hours. Thereaction mixture was cooled and concentrated by rotary evaporation. Thesample was purified by Preparatory Reverse Phase HPLC, then dried underAr stream. Drying in vacuo yielded 0.0845 g of or4-[[5-phenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 209-214° C. (comp. 53).

EXAMPLE B22

[0203] Compound (3) (0.001 mol), tetraethenyl stannane (0.22 ml),1,4-dioxane (2 ml) and Pd(PPh₃)₄ (0.112 g) were combined in a sealedtube under Ar. The mixture was stirred and heated to 100° C. for 16hours. More tetraethenyl stannane and Pd(PPh₃)₄ were added. The reactionwas placed under Ar, stirred and heated. The reaction was concentratedby rotary evaporation and purified on preparative HPLC. The material wasdried with a N₂ stream, and dried under vacuum for 4 hours at 60° C. toobtain 0.422 g of4-[[5-ethenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 237-242° C. (comp. 54).

EXAMPLE B23

[0204] Compound (3) (0.001225 mol), CuCN (0.001470 mol) andN,N-dimethylformamide (2 ml) were combined in a sealed tube under Argon,then stirred and heated to 160° C. for 16 hours. The residue waspurified by column chromatography (eluent: CH₂Cl₂/hexane 1/1, then pureCH₂Cl₂). The desired fractions were collected and the solvent wasevaporated. The residue was triturated under CH₂Cl₂ at room temperature.The solid was dried (vacuum, 40° C., 24 hours, yielding 0.0864 g of

[0205] (24%); mp. 254-259° C. (comp.55).

[0206] Tables 1, 2, 3 and 4 list compounds of formula (I-a) which weremade analogous to one of the above examples. TABLE 1

Comp. Ex. No. No. Y Physical data 1 B1a Cl — 2 B1a Br mp. 227-228° C.22  B11 NO₂ mp. 224-226° C.

[0207] TABLE 2

Co. Ex. No. No. R^(a) R^(b) R^(c) X Y Q mp./salt  3 B1b CH₃ CH₃ CH₃ NHBr H mp. 227-228° C.  4 B2 CH₃ CH₃ CH₃ NH Cl NH₂ mp. 241-242° C.;trifluoroacetate (1:1)  5 B3 CH₃ CH₃ CH₃ NH Cl H mp. 224-226° C.  6 B5CH₃ CH₃ CH₃ O Cl H mp. 218-219° C.  7 B5 CH₃ CH₃ CH₃ S Cl H mp. 264-266°C.  8 B5 CH₃ Br CH₃ O Cl H mp. 237-238° C.  9 B3 CH₃ Br CH₃ NH Cl H mp.217-219° C. 10 B4 Br CH₃ Br NH Cl H mp. 262-263° C. 11 B4 Br Br F NH ClH mp. 200-202° C. 12 B4 CH₃ C(CH₃)₃ CH₃ NH Cl H mp. 214-215° C. 13 B4CH₃ CN CH₃ NH Cl H mp. 281-283° C. 14 B4 Cl Cl CH₃ NH Cl H mp. 243-245°C. 15 B5 Cl Br CH₃ O Cl H mp. 244-247° C. 16 B5 CH₃ Cl CH₃ O Cl H mp.232-235° C. 17 B6 CH₃ CN CH₃ O Br H mp. 288-289° C. 18 B5 CH₃ CN CH₃ OCl H mp. 283-284° C. 19 B7 CH₃ CN CH₃ NH Cl NH₂ mp. 266-268° C.;trifluoroacetate (1:1) 20 B3 Cl Cl CH₃ NH Br H mp. 253-254° C. 21 B3 CH₃Br CH₃ NH Br H mp. 243-245° C. 23 B23 CH₃ CN CH₃ NH CN H mp. 275-290°C.; trifluoroacetate (1:1) 24 B23 CH₃ Br CH₃ NH CN H mp. 291-299° C. 25B14 CH₃ CN CH₃ O Br NH—CH₃ mp. 248-250° C. 26 B14 CH₃ CN CH₃ O Br NH₂mp. 255-256° C. 27 B14 CH₃ CH₃ CH₃ O Br NH₂ — 28 B14 CH₃ CH₃ CH₃ O BrNH—CH₃ mp. 213-214° C. 29 B14 CH₃ CN CH₃ O Br NH—C₂H₅ mp. 263-264° C. 30B14 CH₃ CN CH₃ O Cl NH₂ mp. 272-274° C. 31 B14 CH₃ CH₃ CH₃ O Cl NH₂ mp.199-202° C. 32 B11 CH₃ CH₃ CH₃ NH NO₂ H mp. >300° C. 33 B5 CH₃ CH₃ CH₃ OBr H mp. 207-215° C. 34 B5 CH₃ CH₃ CH₃ O Cl Cl mp. 225-226° C. 35 B5 CH₃CN CH₃ O Cl Cl mp. 273-276° C. 36 B6 CH₃ CN CH₃ O Cl Br mp. 281-282° C.37 B5 CH₃ CH₃ CH₃ O Cl Br mp. 214-215° C. 40 B8 CH₃ CH(CH₃)₂ CH₃ NH Br Hmp. 198° C.; trifluoroacetate (1:2) 41 B10 CH₃ CH₃ CH₃ NH Br Cl mp. 220°C. 42 B9 CH₃ CN CH₃ NH Br Cl mp. 259° C. 43 B11 CH₃ CN CH₃ O NO₂ Hmp. >300° C. 44 B12 CH₃ CN CH₃ O Br CH₃ mp. 260° C. 45 B13 CH₃ CN CH₃ NHBr H mp. 277° C. 46 B14 CH₃ CN CH₃ O Br NH₂ mp. 255° C. 47 B15 CH₃ CNCH₃ O Br

mp. 208° C.; HCl (1:1) 48 B16 CH₃ CN CH₃ O Br —NH—O—CH₃ mp. 185-186° C.49 B17d CH₃ CN CH₃ O —NH—COCH₃ H mp. 290-295° C. 50 B18 CH₃ CN CH₃ O—NH₂ H mp. >300° C. 51 B18 CH₃ CH₃ CH₃ NH —NH₂ H mp. 224-225° C.;trifluoroacetate (1:1) 52 B20 CH₃ CH₃ CH₃ NH CN H mp. 165-175° C. 53 B21CH₃ CH₃ CH₃ NH phenyl H mp. 209-214° C. 54 B22 CH₃ CH₃ CH₃ NH —CH═CH₂ Hmp. 237-242° C.; trifluoroacetate (1:1) 55 B23 CH₃ CH₃ CH₃ NH —CH═CH₂ Hmp. 254-259° C.

[0208] TABLE 3

Comp. Ex. No. No. Z 38 B17C —C(═O)—CH₃ mp. 194-196° C. 56 B17a—CH₂—CO—O—C(CH₃)₃ mp. 195-197° C. 57 B17b —CH═O mp. 232-233° C. 58 B17c—CO—O—C₂H₅ mp. 209-210° C. 59 B6b —CH₂—CO—OC₂H₅ mp. 185-190° C. 60 B6c—CH₂—O—CO—C(CH₃)₃ mp. 168-169° C. 61 B6d —CO—CH₂—OCH₂—CO—OCH₃ mp.184-185° C.

[0209] TABLE 4

Comp. Ex. No. No. R^(a) R^(b) X Y Q 39 B5 Cl Cl S Br H mp. 198-200° C.

[0210] C. Pharmacological Example

EXAMPLE C.1

[0211] A rapid, sensitive and automated assay procedure was used for thein vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cellline, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer,36, 445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\quad {expressed}\quad {in}\quad \%},$

[0212] expressed in %, whereby (OD_(T))_(HIV) is the optical densitymeasured with a given concentration of the test compound in HIV-infectedcells; (OD_(C))_(HIV) is the optical density measured for the controluntreated HIV-infected cells; (O_(DC))_(MOCK) is the optical densitymeasured for the control untreated mock-infected cells; all opticaldensity values were determined at 540 nm. The dose achieving 50%protection according to the above formula was defined as the 50%inhibitory concentration (IC₅₀ in μM). The ratio of CC₅₀ to IC₅₀ wasdefined selectivity index (SI). The compounds of formula (I-A) wereshown to inhibit HIV-1 effectively. Particular IC₅₀, CC₅₀ and SI valuesare listed in Table 5 hereinbelow. TABLE 5 Co. Co. No. IC₅₀ (μM) CC₅₀(μM) SI No. IC₅₀ (μM) CC₅₀ (μM) SI 2 0.030 82.6 2730 10 0.005 0.4 92 30.006 4.4 738 11 0.002 0.4 183 1 0.004 10.9 2787 12 0.020 48.5 2393 40.002 10.0 5555 13 0.0005 0.4 860 5 0.002 0.4 178 14 0.002 0.4 191 60.009 >100 >11049 15 0.010 >100 >9661 7 0.084 >100 >1182 160.010 >100 >10416 8 0.012 >100 >8298 17 0.002 >10 >6451 9 0.003 1.2 37618 0.001 >10 >7142 46 0.002 >200 >71428 60 0.002 74.52 39223 610.002 >100 >52631

1. A compound having the formula

a N-oxide, an addition salt, a quaternary amine or a stereochemicallyisomeric form thereof, wherein -b¹=b²-C(R^(2a))=b³-b⁴=represents abivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═  (b-1);—N═CH—C(R^(2a))═CH—CH═  (b-2);—CH═N—C(R^(2a))═CH—CH═  (b-3);—N═CH—C(R^(2a))═N—CH═  (b-4);—N═CH—C(R^(2a))═CH—N═  (b-5);—CH═N—C(R^(2a))═N—CH═  (b-6);—N═N—C(R^(2a))═CH—CH═  (b-7);q is 0, 1, 2; or where possible q is 3 or 4; R¹ is hydrogen; aryl;formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R^(2a) is cyano, aminocarbonyl, mono- ordi(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano, aminocarbonylor mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano,or C₂₋₆alkynyl substituted with cyano; each R² independently is hydroxy,halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one ormore halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶or a radical of formula

wherein each A independently is N, CH or CR⁶; B is NH, O, S or NR⁶; p is1 or 2; and R⁶ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, whereby each of said aliphatic group may be substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indolyl or isoindolyl, each optionally substituted with one, two, threeor four substituents each independently selected from halo, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl, phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of saidaromatic rings may optionally be substituted with one, two, three, fouror five substituents each independently selected from the substituentsdefined in R²; or L is —X—R³ wherein R³ is phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromaticrings may optionally be substituted with one, two, three, four or fivesubstituents each independently selected from the substituents definedin R²; and X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)— or —S(═O)₂—; Q represents hydrogen, C₁₋₆alkyl, halo,polyhaloC₁₋₆alkyl or —NR⁴R⁵; and R⁴ and R⁵ are each independentlyselected from hydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy,C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- ordi(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein eachof the aforementioned C₁₋₁₂alkyl groups may optionally and eachindividually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het; or R⁴ and R⁵ takentogether may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono-or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; Y represents hydroxy, halo,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms, C₂₋₆alkynyl optionally substituted with one or morehalogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or aryl; aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;Het is an aliphatic or aromatic heterocyclic radical; said aliphaticheterocyclic radical is selected from pyrrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl andtetrahydrothienyl wherein each of said aliphatic heterocyclic radicalmay optionally be substituted with an oxo group; and said aromatichetero-cyclic radical is selected from pyrrolyl, furanyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of saidaromatic heterocyclic radical may optionally be substituted withhydroxy.
 2. A compound as claimed in claim 1 wherein R¹ is hydrogen,aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl.
 3. A compound as claimed in claim 1 or 2 wherein Lis —X—R³ wherein R³ is 2,4,6-trisubstituted phenyl.
 4. A compound asclaimed in any one of claims 1 to 3 wherein Y is cyano, —C(═O)NH₂ or ahalogen.
 5. A compound as claimed in any one of claims 1 to 4 wherein Qis hydrogen or NR⁴R⁵.
 6. A compound as claimed in any one of claims 1 to5 wherein the compound is4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile;4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;or4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;a N-oxide, an addition salt, a quaternary amine and a stereochemicallyisomeric form thereof.
 7. A compound as claimed in any one of claims 1to 6 for use as a medicine.
 8. The use of a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine or a stereochemically isomeric form thereof, wherein-a¹=a²-a³=a⁴-represents a bivalent radical of formula—CH═CH—CH═CH—  (a-1);—N═CH—CH═CH—  (a-2);13N═CH—N═CH—  (a-3);—N═CH—CH═N—  (a-4);—N═N—CH═CH—  (a-5); n is 0, 1, 2, 3or 4; and in case -a¹=a²-a³=a⁴-is (a-1), then n may also be 5; R¹ ishydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;each R² independently is hydroxy, halo, C₁₋₆alkyl optionally substitutedwith cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionallysubstituted with one or more halogen atoms or cyano, C₂₋₆alkynyloptionally substituted with one or more halogen atoms or cyano,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶; B is NH, O, S or NR⁶; p is1 or 2; and R⁶ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, whereby each of said aliphatic group may be substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indolyl or isoindolyl, each optionally substituted with one, two, threeor four substituents each independently selected from halo, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₆alkylcarbonyl, phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of saidaromatic rings may optionally be substituted with one, two, three, fouror five substituents each independently selected from the substituentsdefined in R²; or L is —X—R³ wherein R³ is phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromaticrings may optionally be substituted with one, two, three, four or fivesubstituents each independently selected from the substituents definedin R²; and X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)— or —S(═O)₂—; Q represents hydrogen, C₁₋₆alkyl, halo,polyhaloC₁₋₆alkyl or —NR⁴R⁵; and R⁴ and R⁵ are each independentlyselected from hydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy,C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- ordi(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein eachof the aforementioned C₁₋₁₂alkyl groups may optionally and eachindividually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het; or R⁴ and R⁵ takentogether may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono-or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; Y represents hydroxy, halo,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms, C₂₋₆alkynyl optionally substituted with one or morehalogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or aryl; aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;Het is an aliphatic or aromatic heterocyclic radical; said aliphaticheterocyclic radical is selected from pyrrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl andtetrahydrothienyl wherein each of said aliphatic heterocyclic radicalmay optionally be substituted with an oxo group; and said aromaticheterocyclic radical is selected from pyrrolyl, furanyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of saidaromatic heterocyclic radical may optionally be substituted withhydroxy; for the manufacture of a medicine for the treatment of subjectssuffering from HIV (Human Immunodeficiency Virus) infection.
 9. The useof a compound as claimed in any one of claims 1 to 6 for the manufactureof a medicine for the treatment of subjects suffering from HumanImmunodeficiency Virus infection.
 10. The use of a compound as claimedin any one of claims 1 to 6 wherein R¹ is hydrogen, aryl, formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl for themanufacture of a medicine for the treatment of subjects suffering fromHIV (Human Immunodeficiency Virus) infection.
 11. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically active amount of a compound as claimed in any one ofclaims 1 to
 6. 12. A process for preparing a pharmaceutical compositionas claimed in claim 11 characterized in that a therapeutically effectiveamount of a compound as claimed in any one of claims 1 to 6 isintimately mixed with a pharmaceutically acceptable carrier.
 13. Aprocess for preparing a compound as claimed in claim 1, characterized bya) reacting an intermediate of formula (II) with an amino derivative offormula (III) under solvent-free conditions or in a reaction-inertsolvent under a reaction-inert atmosphere

wherein W¹ is a suitable leaving group and L, Y, Q, R¹, R², R^(2a), qand -b¹=b²—C(R^(2a))=b³-b⁴=are as defined in claim 1; b) reacting anintermediate of formula (IV) with an intermediate of formula (V) undersolvent-free conditions or in an appropriate solvent under areaction-inert atmosphere

wherein W² is a suitable leaving group and Y, Q, R¹, R², R^(2a), R³, qand -b¹=b²—C(R^(2a))=b³-b⁴=are as defined in claim 1; c) reacting anintermediate of formula (IV) with an intermediate of formula (VI) in anappropriate solvent under a reaction-inert atmosphere in the presence ofa suitable base

wherein W² is a suitable leaving group and Y, Q, R¹, R², R^(2a), R³, qand -b¹=b²—C(R^(2a))=b³-b⁴=are as defined in claim 1; or, if desired,converting compounds of formula (I-a) into each other followingart-known transformation reactions; and further, if desired, convertingthe compounds of formula (I-a), into an acid addition salt by treatmentwith an acid, or conversely, converting the acid addition salt form intothe free base by treatment with alkali; and, if desired, preparingstereochemically isomeric forms thereof.
 14. The combination of acompound as defined in claim 1 or 8 and another antiretroviral compound.15. A combination as claimed in claim 14 for use as a medicine.
 16. Aproduct containing (a) a compound as defined in claim 1 or 8, and (b)another antiretroviral compound, as a combined preparation forsimultaneous, separate or sequential use in anti-HIV treatment.
 17. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and as active ingredients (a) a compound as defined in claim 1or 8, and (b) another antiretroviral compound.